Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing CS & ME-TRAP against controlled human malaria infection in malaria naïve individuals

Background.?Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors ChAd63-MVA is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the pre-erythrocytic antigen insert ME-TRAP. We hypothesised that ChAd63-MVA containing CS may result in significant, clinical protective efficacy.Methods.?We conducted an open-label, two-site partially randomized sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP. The study was registered at: www.clinicaltrials.gov (NCT01623557).Results.?1/15 (7%) vaccinees receiving ChAd63-MVA CS and 2/15 (13%) vaccinees receiving ChAd63-MVA ME-TRAP were sterilely protected post-CHMI. 3/15 (20%) vaccinees receiving ChAd63-MVA CS and 5/15 (33%) vaccinees receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment compared to unvaccinated controls. In qPCR analyses, ChAd63-MVA CS was estimated to reduce liver parasite burden by 69-79%, compared to 79-84% for ChAd63-MVA ME-TRAP.Conclusions.?ChAd63-MVA CS does result in a reduction in liver parasite burden but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller, but biologically important differences in vaccine efficacy that can influence future vaccine developmen

Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP

Heterologous prime-boost vaccination with viral vectors simian adenovirus 63 (ChAd63) and Modified Vaccinia Ankara (MVA) induces potent T cell and antibody responses in humans. The 8-week regimen demonstrates significant efficacy against malaria when expressing the pre-erythrocytic malaria antigen Thrombospondin-Related Adhesion Protein fused to a multiple epitope string (ME-TRAP).We tested these vaccines in 7 new 4- and 8- week interval schedules to evaluate safety and immunogenicity of multiple ChAd63 ME-TRAP priming vaccinations (denoted A), multiple MVA ME-TRAP boosts (denoted M) and alternating vectors. All regimes exhibited acceptable reactogenicity and CD8+ T cell immunogenicity was enhanced with a 4-week interval (AM) and with incorporation of additional ChAd63 ME-TRAP vaccination at 4- or 8-weeks (AAM or A_A_M). Induction of TRAP antibodies was comparable between schedules. T cell immunity against the ChAd63 hexon did not affect T cell responses to the vaccine insert, however pre-vaccination ChAd63-specific T cells correlated with reduced TRAP antibodies. Vaccine-induced antibodies against MVA did not affect TRAP antibody induction, and correlated positively with ME-TRAP-specific T cells. This study identifies potentially more effective immunisation regimens to assess in Phase IIa trials and demonstrates a degree of flexibility with the timing of vectored vaccine administration, aiding incorporation into existing vaccination programmes.</p

Evaluation of the efficacy of chad63-mva vectored vaccines expressing circumsporozoite protein and me-trap against controlled human malaria infection in malaria-naive individuals

Background: Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy. Methods: We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP. Results: One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%–79%, compared with 79%–84% for ChAd63-MVA ME-TRAP. Conclusions: ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development. Clinical Trials Registration: NCT01623557. </p